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Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease

Nature Medicine volume 30, pages 1199–1209 (2024)Cite this article

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Abstract

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016–2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9–76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

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Fig. 1
Fig. 2: Effects of fixed-dose combination therapy on the risk of all-cause mortality and ASCVD events.
Fig. 3: Effects of fixed-dose combination therapy on SBP and LDL-C.
Fig. 4: Effects of fixed-dose combination therapy on adverse events and adherence.

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Data availability

We conducted the searches on MEDLINE (Ovid), Cochrane Library (Wiley), EMBASE (Elsevier), CINAHL Plus with Full Text (EBSCOhost) and Web of Science (Thomson Reuters). We sought additional studies from ClinicalTrials.gov and the World Health Organization International Clinical Trial Registry Platform. Search results were uploaded to EndNote (version 20) and subsequently Covidence (available from https://www.covidence.org/) for deduplication and screening. Data supporting the findings of this study are available within the manuscript, extended data and Supplementary Information. Any additional data are available from the corresponding author upon request by email.

Code availability

Custom code was developed using R version 4.0.5 (R Project for Statistical Computing) for analysis of data inputs. The statistical code used for this analysis is available at https://github.com/THUYE/FDC-Therapy-ASCVD.

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Acknowledgements

We thank the investigators of the PolyIran-Liver trial for sharing selected disaggregated data to allow our team to standardize definitions of ASCVD events in this systematic review and meta-analysis. We thank A. Hively for his contributions in manuscript reviewing. The study received no funding. A.A. is supported by the NIH/NHLBI grant K99HL157687 and has received funding from grant 2020144 from the Doris Duke Charitable Foundation.

Author information

Authors and Affiliations

  1. Department of Medicine and Global Health Center, Washington University in St. Louis, St. Louis, MO, USA

    Anubha Agarwal, JingJing Zhu & Mark D. Huffman

  2. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Priya M. Mehta, Tyler Jacobson & Nilay S. Shah

  3. Weill Cornell Medicine, New York, NY, USA

    Jiancheng Ye

  4. Galter Health Sciences Library and Learning Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Q. Eileen Wafford

  5. Desert Cardiology Consultants, Eisenhower Medical Center, Rancho Mirage, CA, USA

    Ehete Bahiru

  6. Department of Psychiatry, University of Oxford, Oxford, UK

    Angharad N. de Cates

  7. Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

    Shah Ebrahim

  8. Centre for Chronic Disease Control, New Delhi, India

    Dorairaj Prabhakaran

  9. Public Health Foundation of India, Gurgaon, India

    Dorairaj Prabhakaran

  10. The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia

    Anthony Rodgers & Mark D. Huffman

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Contributions

A.A., A.N.d.C., S.E. and M.D.H. conceptualized the study and designed the systematic review protocol. Q.E.W. performed all database searches. A.A., P.M.M., T.J., N.S.S, J.Z., E.B. and M.D.H. contributed to screening, data extraction and quality of evidence assessment. J.Y. conducted the meta-analysis and provided statistical expertise. A.A. led writing of the original draft and P.M.M., T.J., N.S.S., J.Y., J.Z., Q.E.W., E.B., A.N.d.C., S.E., D.P., A.R. and M.D.H. contributed to revising the manuscript critically for important intellectual content. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Anubha Agarwal.

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Competing interests

M.D.H. has received travel support from the World Heart Federation. M.D.H. and A.R. have an appointment at The George Institute for Global Health, which has a patent, license and has received investment funding with intent to commercialize fixed-dose combination therapy through its social enterprise business, George Medicines. George Health Enterprises Pty Ltd, the social enterprise arm of the George Institute for Global Health (TGIGH), has received investment to develop fixed-dose combination products containing aspirin, statin and BP-lowering drugs. The George Institute for Global Health holds and have filed applications for combination products for the treatment of hypertension and diabetes, and A.R. is listed as one of the inventors (granted: US 10,369,15; US 10,799,487; US 10,322,117; US 11,033,544; and US 11,478,462 and pending: US 17/932,982; US 18/446,268; US 17/598,122; and US 17/317,614). A.R. is seconded part-time to George Medicines Pty Ltd, a subsidiary of George Health Enterprises. A.R. does not have a personal financial interest in these patents or products. M.D.H. and A.A. have pending patents for heart failure polypills. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Sensitivity analyses of primary outcomes including only large studies with more than 500 participants.

Shown are risks of fatal or non-fatal ASCVD events in mostly primary prevention trials [N = 3 studies, N = 14,817 participants] (a). Shown are effects on systolic blood pressure in mostly primary prevention trials (b). Shown are effects on systolic blood pressure in mixed secondary prevention trials (c). Shown are effects on LDL cholesterol in mostly primary prevention trials (d). Shown are effects on LDL cholesterol in mixed secondary prevention trials (e). Shown are effects on adverse events in mostly primary prevention trials [N = 3 studies, N = 13,140 participants] (f). Shown are effects on adverse events in mixed secondary prevention trials [N = 5 studies, N = 6,301 participants] (g). Shown are effects on adherence in mostly primary, mixed, and secondary prevention trials [N = 6 studies, N = 11,280 participants] (h). In these forest plots, the risk ratio or mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall risk ratio or mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 2 Effects of fixed-dose combination therapy on diastolic blood pressure: primary analyses.

Shown are effects on diastolic blood pressure (mmHg) in mostly primary prevention trials (a) and mixed secondary prevention trials (b). In these forest plots, the mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 3 Effects of fixed-dose combination therapy on total cholesterol: primary analyses.

Shown are effects on total cholesterol (mmol/L) in mostly prevention trials (a), mixed secondary prevention trials (b), trials with comparator as usual care (c), and trials evaluating three-drug or more fixed-dose combination therapies (d). In these forest plots, the mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 4 Effects of fixed-dose combination therapy on discontinuation.

In this forest plot (N = 9 studies, N = 8,927 participants), the risk ratio for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall risk ratio is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 5 Effects of fixed-dose combination therapy on health-related quality of life using EQ-5D health state.

In this forest plot, the mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 6 Effects of fixed-dose combination therapy on the risk of all-cause mortality and atherosclerotic cardiovascular disease events: subgroup analyses.

Shown is the risk of all-cause mortality in trials with comparator as usual care [N = 7 studies, N = 16,171 participants] (a). Shown is the risk of all-cause mortality in trials evaluating three-drug or more fixed-dose combination therapies [N = 8 studies, N = 21,122 participants] (b). Shown is the risk of fatal and non-fatal ASCVD events in trials with comparator as usual care [N = 6 studies, N = 14,720 participants] (c). Shown is the risk of fatal and non-fatal ASCVD events in trials evaluating three-drug or more fixed-dose combination therapies [N = 9 studies, N = 21,603 participants] (d). In these forest plots, the risk ratio for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall risk ratio is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 7 Effects of fixed-dose combination therapy on systolic blood pressure: subgroup analyses.

Shown is the effect on systolic blood pressure (mmHg) in trials with comparator as usual care (a) and effect on systolic blood pressure (mmHg) in trials evaluating three-drug or more fixed-dose combination therapies (b). In these forest plots, the mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 8 Effects of fixed-dose combination therapy on LDL cholesterol: subgroup analyses.

Shown is the effect on LDL cholesterol (mmol/L) in trials with comparator as usual care (a). Shown is the effect on LDL cholesterol in trials evaluating three-drug or more fixed-dose combination therapies (b). In these forest plots, the mean difference for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall mean difference is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 9 Effects of fixed-dose combination therapy on adverse events as defined by study investigators: subgroup analyses.

Shown are effects on any adverse event in trials with the comparator as usual care [N = 7 studies, N = 13,308 participants] (a). Shown are effects on any adverse event in trials evaluating three-drug or more fixed-dose combination therapies [N = 13 studies, N = 19,697 participants] (b). Shown are effects on adverse event of myalgias [N = 12 studies, N = 11,204 participants] (c). Shown are effects on adverse event of increased liver enzymes [N = 6 studies, N = 2,280 participants] (d). Shown are effects on adverse event of cough [N = 7 studies, N = 10,967 participants] (e). Shown are effects on adverse event of dyspepsia/gastrointestinal irritation [N = 8 studies, N = 15,567 participants] (f). Shown are effects on adverse event of bleeding [N = 5 studies, N = 9,473 participants] (g). In these forest plots, the risk ratio for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall risk ratio is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

Extended Data Fig. 10 Effects of fixed-dose combination therapy on adherence: subgroup analysis.

In this forest plot [N = 4 studies, N = 4,872 participants], the risk ratio for each individual study is represented with an orange dot surrounded by a dark blue square representing the weight assigned to each study in the model, with 95% confidence intervals represented by horizontal lines. The overall risk ratio is represented by a green diamond. All statistics were based on a two-sided z-test with no adjustments made for multiple comparisons.

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Supplementary Tables 1–4 and Figs.1–3.

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Agarwal, A., Mehta, P.M., Jacobson, T. et al. Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease. Nat Med 30, 1199–1209 (2024). https://doi.org/10.1038/s41591-024-02896-w

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